d-chondocurarine halides and process for making same



Patented May 4, 1948 d-CHONDOCURARINE HALIDES AND PROCESS FOR MAKINGSAME Oskar Wintcrsteiner and James D. Dutcher, New Brunswick, N. J.,assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of NewYork No Drawing. Application March 16, 1943, Serial No. 479,378

4 Claims. (c1. 260-236) This invention relates to derivatives of theourare alkaloids.

Curare is a plant extract characterized by a relaxing (lissive) effecton the musculature. It has been used, with good results, in thetreatment of spastic paralysis, a distressing condition frequentlyfollowing cerebral injuries at childbirth, and also in combination withanesthesia during surgical operations; and it has come into medicalprominence lately as a means for moderating the convulsions in theshock-therapy of certain psychoses.

The therapeutic use of curare, though promising, was limited because ofthe difficulty of providing curare preparations of constant compositionand potency; a difficulty due primarily to the uncertain botanicalorigin of the available crude curare preparations, which had to besupplied by explorers, and to the contamination of these preparationswith other poisons, snake venoms, and other materials, active andinactive. Constant potency and identical action is essential for thetherapeutic utility of a curare preparation, since curares margin ofsafety (the range of dosage between that giving the desiredskeletal-muscle eifect and that giving the undesirable toxic paralysisof the muscles of respiration) is very small.

As disclosed in application Ser. No. 442,094, filed May 7, 1942, nowabandoned, it was found that curare preparations of constant compositionand high potency, and particularly crystalline d-curarine chloride,could be obtained from the plant Chondodendron tomentosum (known to theAmazonian Indians as Ampi Huasca), especially if the plant were used inthe fresh (rather than dried) state; and as a by-product there wereobtained certain novel tertiary bases of negligible lissive potency, andthese bases were isolated in pure form, and identifiedas follows:

(1) A crystalline tertiary base which melts at 232-234 C. and has an [a]+190 in normal HCl.

(2) A crystalline tertiary base which has the empirical formulaCasHaaOsNz, melts at 160 C., and has an [M -167 in chloroform.

These bases may be obtained as follows: 100

O OH:

kg. fresh, green liana stems of Chondodendron tomentosum (Ampi Huasca)is cut into pieces of convenient size and extracted with water that hasbeen acidified to pH about 5 with hydrochloric acid. The extract isconcentrated until about 4 kg. of a syrupy or molasses-like liquid isobtained, and then carefully brought to dryness in vacuo at 60 C. Theresulting dry brown powder, a crude curare, constitutes about half theweight of the syrup. 50 g. of the crude curare is exhaustively extractedat room temperature with 400 cc. portions of a 1% aqueous solution oftartaric acid. The dark brown extract is filtered to remove insolublematerial (about 2.5 g.) made alkaline by the addition of saturatedsodium bie carbonate solution, and exhaustively extracted withchloroform; and the extract is separated from the aqueous phase. Thechloroform extract contains about 3 g. of extracted material comprisingtertiary bases of comparatively low lissive potency. On dissolving theextractedmaterial in methanol, a crystalline deposit is formed; andafter chilling for several hours, the crystalline material (weighingabout 500 mg.) is separated by filtration. The crystalline material,after recrystallization from hot methanol, melts at 232-234 C., has an[u] |190 in normal hydrochloric acid, and has theempirical formula CaHssOeNz. The residue, obtained by evaporating the methanolic motherliquor, is dissolved in benzene and chromatographed on A1203. Thefraction (about 500 mg.) eluted with benzene containing 1 methanolyields, after purification b recrystallization from hot benezene orchloroform, a tertiary base, CssHssOsNz, melting at C. and having an [mi-167 in chloroform.

It has now been found that these tertiary bases may be converted intonovel quaternary halides of high lissive potency, and that the dimethylethers of these halides have an extraordinarily high lissive potency.

Thus, base (1) above (which is now known to have the empirical formulaCssI-IzsOeNz and to possess two free phenolic hydroxy groups and twomethoxy groups, and has been named-and will hereinafter be referred toas-d-chondocurine) has been converted into a quaternary iodide which hasthe empirical formula C3BH44O6N2I2 and is believed to have the(bisbenzylisoquinoline) structural formula.

(CH2): OR OR H om-O-o O +N H, (halogen)z= R'OQ/ (0H0: 0 V

wherein R and one of the HS is hydrogen and the other R. is methyl. Thecorresponding quaternary base has been named-and will hereinafter bereferred to as--d-chondocurarine.

Whereas.d-chondocurineis practically .completely' devoid of lissiveactivity, d-chondocurarine iodide has a potency of 20 Holaday units permg. in

the rabbit, i. 6., about three times the potency of d-tubocurarinechloride. d-Chondocurarine chloride has the same potency asd-chondocurarine iodide, when allowance is made for the difference inweight of the anions.

mined by the cross-over rabbit-head-drop method of Holaday applicationSeria1No. 396,871 filed June 6, 1941, now Patent'f No; 2397,4117, datedMarch 26, 1946.]

EXAMPLE "2 Preparation of d-chondocurarine chloride d-Chondocurarineiodide is shaken with an -I' excess of freshly precipitated silverchloride in .silver-iodideand excess silver chloride, the aque- V a oussolution is concentrated to dryness in vacuo. [The Potencles referred toherem w e. d te 1'" The residue, .d-chondocurarine chloride(dchondocurine dime'thochloride) is a colorless, viscous syrup whichdoes not crystallize, is very sol- .ubl-ein-water, and has an [u] [-175in water.

Similarly, base 2 (which is isomeric with quaternary bases having noappreciable lissive activity.

'It has been found, also, that these quaternary bases-edechondocurarinehalidesand the isomeric quaternary bases derived from tertiary base (2)may .be further methylated '(on the two free phenolic hydroxy ,groups)'toobtain thej corresponding dimethylethers (i: e., compounds in whichall four phenolic hydroxy groups are methylated) andthat thesedimethylethers have" lissive .potencies (in the rabbit) many times thatof the parent quaternary bases. Thus, further methylation of 'dchondocurarine iodide (dchondocurine dimethiodide) results in a.threefold increase ,inlissive potency :(in the rabbit) and theresulting compound'has been found to.

be identical with the d-tuboourarine dimethylether iodide,heretoforeyprepared from d-tub'ocurarine iodide '(cf. sectionj ofExamplel in application Ser. No. $42,094). The compounds dtubocurarineiodide andd-tubocurarine dimethylether iodide, are believed to "have thestructural formula given ihereinbefore, wherein 'R' and one.

of the'Rfs ishydrogen, and theotherR is methyl, and wherein R andhothRsare methyl (respectively). 1 Q Q The following examplesare' illustrativeof the invention; j

EXAMPLE 1' Preparation of d-chondocur rine iodide 500 .mg. .ofcrystalline .d-chondocurine :(the tertiary base melting .at 232-234" C.described in section g, Example 1 of application Ser. No. 442,- 094) isdissolved iii-methanol, ml. methyl iodide is added, and the reactionmixture is refluxed for two hours. The methanol and excess methyl iodideare than removed by vacuum distillation; the amorphous residue isextracted with hot water, and the hot extract is treated with a" smallamount of charcoal, and filtered. On cooling, d-chondocurarine iodide'(d-chondocurine' dimethiodide) is obtained as a nearly colorlessamorphous precipitate, melting at 275 C. (with decomposition) and havingan [al +180 in methanol. Addition of some potassium iodide to theoriginal ,hot solution increases the yield of the product (by loweringthe solubility) almost to quantitative. u

EXAMPLE 3 Preparation of d-tulrocurarine dimethylether iodide fromd-chondocurine The product is identical with that obtained fromd-tubocurarine .iodide by methylation of the two free phenolic hydroxygroups.

' ExAMrLE 4 Preparation of the dimethiodide of tertiary 'base (2) 50mg.of tertiary base (2) the tertiary base melting at 160 C. (orthe purerform" melting at 167? C.) disclosed in section g, Example 1 ofapplication Ser. No. 442,094 is dissolved in 0.1 ml. methyl iodide; andon standing 12-16 hours at room temperature, the quaternary base iodide("dimethiodidw deposits in quantitative yield as long, colorlessneedles. After washing free .of excess methyl iodide and drying invacuo, the product :melts at 250 'C. (with decomposition) and has an[00]D-"I35 in methanol.

EXAMPLEE Preparation of the dimethylether dimethiodidc of iertiarybafie('2) mg. of the crystalline dimethiodide obtained in Example 4 isdissolved m2 m1. methanol, and 3;!) ml. 0.5 normal methanolio KOH and0.5 ml. methyl iodide are added; and. after refluxing the solution foran hour, half as much again of the KOH and methyl iodide are added, andthe refluxing continued for another hour. The solvent is then removed byvacuum distillation, and the residue extracted with small aportions ofhotwater; .andon cooling the aqueous extract, the dimethylether isobtained as an amorphous precipitate fairly soluble in water but less inpotassium iodide solution.

The methyl iodide used in the foregoing examples for the preparation ofthe dimethylethers may be replaced by ethyl iodide or .propyl iodide toobtain the corresponding compounds wherein R, and one of the Rs in thestructural formula given herein-before represent ethyl or propyl. d-Tubocurarine diethylether iodide, thus obtained, has a lissive potency(in the rabbit) higher than that of d-tubocurarine chloride.

The tertiary base tdimethohalides described hereinbefore and their zdiethers may be empioyed clinically as lissive agents for the voluntarymusculature in the same manner as d-tubocurarine chloride; e. g., by theslow intravenous infusion of their aqueous solutions of suitableconcentration (based on the lissive potency of the compound in thehuman).

The invention may be variously otherwise embodied within the scope ofthe appended claims.

We claim:

1. A d-chondocurarine halide having the empirical formula C3sH440sN2(halogen) 2, being the dimethohalide of d-chondocurine, a. tertiary baseobtained from Chondodendron tomentosum and melting at 232-234; C.

2. d-Chondocurarine chloride, having the empirical formulaC38H44OBN2C12, a colorless, viscous, highly water-soluble syrup, beingthe dimethochloride of d-chondocurine, a tertiary base obt tained fromChondodendron tomentosum and melting at 232-234" C.

3. d-Chondocurarine iodide, having the e pirical formula C3sH44OsN2I2and melting with decomposition at 275 (2., being the dimethiodide ord-chondocurine, a tertiary base obtained from Chondod'endron tomentosumand melting at 232-234 C.

4. The method which comprises reacting methyl iodide withd-chondocurine, a tertiary base obtained from Chondodendron tomentosumhaving the empirical formula C'ssHosOeNz and melting at 232-234 C.

OSKAR WINTERSTEINER. JAMES D. BUTCHER.

REFERENCES CITED The following references are of record in the file ofthis patent:

J. Chem. Soc. (London) 1935; pp. 1381-1389. J. Chem. Soc. (London) 1937;pp. 1472-1482. Science, May 21, 1943; pages 467-470.

Certificate of Correction Patent No. 2,440,708.

OSKAR WINTERSTEINER ET AL.

It is hereby certified that errors appear in the printed specificationof the above numbered patent requiring correction as follows: Column 2,line 46, strike out the May 4, 1948 period after the Word formula; samecolumn, in the formula, upper left-hand ring, for

read i lower right-hand ring, for

+ read and that the said Letters Patent should be read with thesecorrections therein that th of the case in the Patent Oflice. 13th dayof July, A. D. 1948.

THOMAS F. MURPHY,

Assistant O'ommz'ssz'oner of Patents.

